Alessandro Roberto Dodesini

Glomerular Hyperfiltration and Renal Disease Progression in Type 2 Diabetes

OBJECTIVE To describe the prevalence and determinants of hyperfiltration (glomerular filtration rate [GFR] ≥120 mL/min/1.73 m2), GFR decline, and nephropathy onset or progression in type 2 diabetic patients with normo- or microalbuminuria. RESEARCH DESIGN AND METHODS We longitudinally studied 600 hypertensive type 2 diabetic patients with albuminuria <200 μg/min and who were retrieved from two randomized trials testing the renal effect of trandolapril and delapril. Target blood pressure (BP) was <120/80 mmHg, and HbA1c was <7%. GFR, albuminuria, and glucose disposal rate (GDR) were centrally measured by iohexol plasma clearance, nephelometry in three consecutive overnight urine collections, and hyperinsulinemic euglycemic clamp, respectively. RESULTS Over a median (range) follow-up of 4.0 (1.7–8.1) years, GFR declined by 3.37 (5.71–1.31) mL/min/1.73 m2 per year. GFR change was bimodal over time: a larger reduction at 6 months significantly predicted slower subsequent decline (coefficient: −0.0054; SE: 0.0009), particularly among hyperfiltering patients. A total of 90 subjects (15%) were hyperfiltering at inclusion, and 11 of 47 (23.4%) patients with persistent hyperfiltration progressed to micro- or macroalbuminuria versus 53 (10.6%) of the 502 who had their hyperfiltration ameliorated at 6 months or were nonhyperfiltering since inclusion (hazard ratio 2.16 [95% CI 1.13–4.14]). Amelioration of hyperfiltration was independent of baseline characteristics or ACE inhibition. It was significantly associated with improved BP and metabolic control, amelioration of GDR, and slower long-term GFR decline on follow-up. CONCLUSIONS Despite intensified treatment, patients with type 2 diabetes have a fast GFR decline. Hyperfiltration affects a subgroup of patients and may contribute to renal function loss and nephropathy onset or progression. Whether amelioration of hyperfiltration is renoprotective is worth investigating.

Lipids and Renal Disease

Chronic renal disease is accompanied by characteristic abnormalities of lipid metabolism, which appear as a consequence of nephrotic syndrome or renal insufficiency and are reflected in an altered apolipoprotein profile as well as elevated plasma lipid levels. Experimental and clinical studies have suggested a correlation between the progression of renal disease and dyslipidemia. High cholesterol and triglyceride plasma levels have been demonstrated to be independent risk factors for progression of renal disease in humans. The underlying pathophysiologic mechanisms for the relationship between lipid levels and progression of renal disease are not yet fully understood, although there are data that oxidative stress and insulin resistance may mediate the lipid-induced renal damage. In the animal model, lipid-lowering agents seem to ameliorate glomerular damage, preventing glomerulosclerosis and interstitial fibrosis. Although evidence from clinical studies indicates that statin therapy is associated with significant benefit in individuals with established chronic renal failure, whether lipid reduction can slow the renal functional decline awaits a primary renal outcome lipid-lowering therapy study.

Measurable Urinary Albumin Predicts Cardiovascular Risk among Normoalbuminuric Patients with Type 2 Diabetes

Micro- or macroalbuminuria is associated with increased cardiovascular risk factors among patients with type 2 diabetes, but whether albuminuria within the normal range predicts long-term cardiovascular risk is unknown. We evaluated the relationships between albuminuria and cardiovascular events in 1208 hypertensive, normoalbuminuric patients with type 2 diabetes from the BErgamo NEphrologic Diabetes Complication Trial (BENEDICT), all of whom received angiotensin-converting enzyme inhibitor (ACEI) therapy at the end of the trial and were followed for a median of 9.2 years. The main outcome was time to the first of fatal or nonfatal myocardial infarction; stroke; coronary, carotid, or peripheral artery revascularization; or hospitalization for heart failure. Overall, 189 (15.6%) of the patients experienced a main outcome event (2.14 events/100 patient-years); 24 events were fatal. Albuminuria independently predicted events (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.02-1.08). Second-degree polynomial multivariable analysis showed a continuous nonlinear relationship between albuminuria and events without thresholds. Considering the entire study population, even albuminuria at 1-2 μg/min was significantly associated with increased risk compared with albuminuria <1 μg/min (HR, 1.04; 95% CI, 1.02-1.07). This relationship was similar in the subgroup originally randomly assigned to non-ACEI therapy. Among those originally receiving ACEI therapy, however, the event rate was uniformly low and was not significantly associated with albuminuria. Taken together, among normoalbuminuric patients with type 2 diabetes, any degree of measurable albuminuria bears significant cardiovascular risk. The association with risk is continuous but is lost with early ACEI therapy.

Effects of Manidipine and Delapril in Hypertensive Patients With Type 2 Diabetes Mellitus The Delapril and Manidipine for Nephroprotection in Diabetes (DEMAND) Randomized Clinical Trial

To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications, we compared glomerular filtration rate (GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with albuminuria <200 mg/min included in a multicenter, double-blind, placebo-controlled trial (DEMAND [Delapril and Manidipine for Nephroprotection in Diabetes]) and randomized to 3-year treatment with manidipine/delapril combination (10/30 mg/d; n=126), delapril (30 mg/d; n=127), or placebo (n=127). GFR was centrally measured by iohexol plasma clearance. Median monthly GFR decline (interquartile range [IQR]) was 0.32 mL/min per 1.73 m2 (IQR: 0.16–0.50 mL/min per 1.73 m2) on combined therapy, 0.36 mL/min per 1.73 m2 (IQR: 0.18–0.53 mL/min per 1.73 m2) on delapril, and 0.30 mL/min per 1.73 m2 (IQR: 0.12–0.50 mL/min per 1.73 m2) on placebo (P=0.87 and P=0.53 versus combined therapy or delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses. Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined therapy and placebo was 0.17 (0.04–0.78; P=0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 (0.07–0.99; P=0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 (0.24–0.87; P=0.017) and 0.52 (0.27–0.99; P=0.048), respectively. Glucose disposal rate decreased from 5.8±2.4 to 5.3±1.9 mg/kg per min on placebo (P=0.03) but did not change on combined or delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity.

Bolus calculator improves long-term metabolic control and reduces glucose variability in pump-treated patients with Type 1 diabetes

Recently insulin pumps were added with bolus calculator to determine the insulin dose, taking into account current and target blood glucose, carbohydrate intake, carbohydrateto-insulin ratio, insulin sensitivity factor (ISF) and duration of insulin action. Few studies evaluated the clinical usefulness of this tool [1e3]. We evaluated one-year efficacy of bolus calculator on long-term glycemic control and glucose variability in 30 Type 1 diabetic patients (17 males, 13 females, age 44 12 years, duration of diabetes 25 10 years) already treated with continuous subcutaneous insulin infusion (CSII) (duration of CSII 64 14 months) that started using a bolus calculator. All patients, already trained to “carbohydrate counting” and ISF to determine insulin dosing, received a 2-h individual education session before switching from a pump without bolus calculator to a new pump with automated bolus calculator. Physicians set up bolus parameters. ISF was calculated using the ratio 1700/daily insulin dose and subsequently modified (when necessary) based on individual blood glucose measurements. HbA1c, BMI, insulin requirement and severe hypoglycemia were evaluated every three months the year before and after the use of bolus calculator. Three seven-point capillary blood glucose profiles and glucose variability (determined by interstitial glucose concentration measured continuously over 72 h) were assessed one month before and after one-year of bolus calculator usage. Both meal composition and the amount of carbohydrates at breakfast, lunch and dinner were similar on those days. Also duration and intensity of exercise were reproducible. Glucose variability was calculated by continuous overall net glycemic action (CONGA2 and CONGA4), evaluated in the temporal division between day (0700e2300 h) and night (2300e0700 h) [4] and mean of daily differences (MODD) [5]. Data are expressed as mean SD. Differences between means were tested using the paired t test or analysis of variance.

Poor Glucose Control in the Year Before Admission as a Powerful Predictor of Amputation in Hospitalized Patients With Diabetic Foot Ulceration

Although there is a strong association between lower-extremity amputation (LEA) and HbA1c (A1C) in diabetic patients (1,2), little information is available on glucose control in the period preceding and following LEA (3). Our objective was to evaluate the predictors of LEA and to examine the role of blood glucose control during the year before and the year after admission. A total of 122 diabetic patients (82 men and 40 women aged 69.7 ± 10.9 years, disease duration 19.7 ± 10.4 years) consecutively admitted for diabetic foot ulcers to the Medicine Department of United Hospitals of Bergamo between January 2003 and December 2004 were enrolled in our observational study and assigned to one …

Continuous Subcutaneous Insulin Infusion Is Better Than Multiple Daily Insulin Injections in Reducing Glucose Variability Only in Type 1 Diabetes With Good Metabolic Control

A possible advantage of continuous subcutaneous insulin infusion (CSII) therapy in type 1 diabetes is the decrease of glucose excursions with respect to multiple daily injections (MDI) of insulin. Few studies investigated this aspect of insulin treatment using continuous glucose monitoring systems (1). The aim of our study was to evaluate whether CSII reduces glucose variability with respect to MDI, in patients with comparable A1C levels. The analysis was conducted in 36 type 1 diabetic patients, treated with CSII (15 male and 21 female subjects, aged 35 ± 12 years, duration of diabetes 16 ± 11 years, A1C 8.3 ± 1.5%) and 77 patients treated with MDI (35 male and 42 female subject, aged 40 ± 15 years, duration of …

The Hyperfiltering Kidney in Diabetes

Hyperfiltering kidney is a typical feature of diabetes. Improvement observed with regard to glucose control and blood pressure control reduces the high glomerular filtration rate and may contribute to retard the appearance and the progression of diabetic renal disease. Although the mechanism of hyperfiltration is still unclear, there is mounting evidence that the increased reabsorption of glucose and sodium by sodium glucose transporter-2 (SGLT-2) is involved in this altered renal function. There is a possibility that SGLT-2 inhibition may correct hyperfiltration in diabetes, adding a new therapeutic approach to halt renal disease in patients with diabetes.